Melanoma is a common cancer of the skin resulting in high morbidity and mortality. Melanomas are malignancies of melanocytes, the specialized pigment cells of the skin, located at the basal layer of the epidermis and which originate from neural crest. Melanoma is one of the most aggressive cancer types in human. Melanoma accounts for only about 4% of skin cancer cases but for as many as 74% of all skin cancer deaths. In 2002, the WHO estimated 160,000 new cases of malignant melanoma worldwide and reported 41,000 deaths caused by this dreadful disease (Parkin D. M. et al). It is the cancer type with the highest increase in incidence: of all cancer in the United States, cutaneous melanoma ranks fifth in incidence among men and seventh among women and is the second leading cause of lost productive years. Recent estimates suggest a doubling of melanoma incidence every 10-20 years (Garbe C. et al). If melanoma can be diagnosed early, it can be cured by surgical excision and this is what occurs in appr. 80% of the cases. However, metastatic melanoma is refractory to current therapies and has a very poor prognosis with a median survival rate of 6 months. Both due to the high propensity to metastisize as well as resistance to available therapies, melanoma represents a great problem for oncology.
Several genes have been implicated in the development of melanoma. The most common tumor suppressor gene involved in melanoma is p16ink4a, encoded by the CDKN2A locus. The CDKN2A locus on human chromosome 9p21 encodes two proteins, p16ink4a and p14ARF, that mainly regulate cell cycle progression and cell survival via the pRb and p53 pathways, respectively. Loss of p16 is accomplished through deletion, mutation or promoter methylation. Mutations in the p14ARF tumor suppressor gene also play a role in melanoma, independent of the effect of the p16ink4a gene. The most commonly mutated oncogenes in melanoma are BRAF and N-RAS (Q61K/R), which are generally mutually exclusive. Interestingly, BRAF is mutated in ˜70% of malignant melanomas, papillary thyroid cancer (36-53%), serous ovarian cancer (˜30%) and colorectal cancer (5-22%), of which the majority is the V600E mutation. In addition, other BRAF mutations have also been detected in, serous ovarian cancer (30%) and lung cancer (3%) (Garnett M. J. et al). However, there are in at least 35 other amino acids within the BRAF protein that are targets for mutations in melanoma (Dhomen N. et al). The V600E mutation results in constitutively active BRAF and has been shown to act as an oncogene in melanocytes. As a consequence of the somatic mutations of BRAF and N-RAS, the RAS-RAF-MEK-ERK MAPK signal transduction pathway, that controls a variety of biological responses, including proliferation and survival, is constitutively active. The aberrant activation of this pathway results in increased proliferation and survival, but also represents an attractive molecular target for melanoma treatment. The importance of MAPK activation in melanoma was shown by inhibiting BRAF with RNAi and inhibiting BRAF or MEK with small molecule inhibitors (Hingorani S. R. et al., Karasarides M. et al.,). Such treatments block cell proliferation, survival, induce apoptosis and inhibit anchorage independent growth. Additional pathways that are aberrantly activated in melanoma are the PI3K/PTEN/Akt pathways. The phosphoinositide-3-kinase (PI3K) and mitogen-activated protein (MAP) kinase pathways are two key signaling cascades that have been found to play prominent roles in melanoma development. Therefore, members of the PI3K signaling pathway may also function as interesting targets for therapeutic intervention (Madhunapantula S. V. et al).
At present, enormous efforts are taken to unravel the molecular mechanisms that lead to changes in cellular processes and the resulting malignant behaviour of transformed melanocytes. One family of molecules involved in the genesis and progression of melanoma cells, the miRNAs, is currently attracting a lot of attention.
miRNAs are naturally occurring single-stranded, non-coding small RNA molecules that control gene expression by binding to complementary sequences in their target mRNAs, thereby inhibiting translation or inducing mRNA degradation. miRNAs have recently emerged as key regulators of gene expression during development and are frequently misexpressed in human disease states, in particular cancer. Recently, WO2012/005572 described several miRNA molecules that could be used for treating diseases or conditions associated with activated BRAF pathway in a subject.
There is currently no effective known medicament that may be used for specifically preventing, treating, regressing, curing and/or delaying a disease or condition associated with melanoma or for diseases or conditions associated with activated BRAF pathway in a subject. The only standard treatments comprise chemotherapy, radiotherapy, surgery. Therefore, there is still a need for new treatments of disease or conditions associated with melanoma.